1. Field of the Invention
The present invention provides a composition of hyaluronic acids in combination with a drug for treating and preventing an inflammation related disorder, especially where the onset of the disorder mainly occurs in mucosal tissue.
2. Description of the Prior Arts
Hyaluronic acid, also known as hyaluronan, hyaluronate and sodium hyaluronate, is generally referred to as HA, which is a natural glycosaminoglycan macromolecule including disaccharides composed of the alternative N-acetyl-D-glucosamine and D-glucuronic acid linked via alternative β-1,3 and β-1,4 glycosidic bonds. HA found in nature with a molecular weight (Mw) between 50,000 Dalton (Da) and a few millions Dalton usually has high viscosity.
HA found in nature is the extra-cellular material with elasticity, filling between the cells and the collagenous fibers and covering onto some epidermal tissues, mainly for protecting and lubricanting cells, for providing a platform for transporting the regulatory T cell, and also for stabilizing collagen network and protecting collagen network from the mechanical damage. HA is also a major lubricant in the tendon and the tendon sheath and on the surface of the synovial membrane due to the lubricant feature and the high shock absorber, and HA is helpful for the tissue rheological mechanics, motion and the cell proliferation (referring to Delpech, B. et al., 1997. Hyaluronan: fundamental principles and applications in cancer. J Intern. Med. 242, 41-48), and participates in the receptor interaction on the surface of some cells, particularly to be the major receptor of CD44. CD44 is widely accepted as a marker of the activated lymphocyte (referring to Teder P, et al., 2002, Resolution of lung inflammation by CD44. Science).
Recently, HA is applied in clinical treatment in the sodium salt form mainly in eye, skin, orthopedics, surgery, arthritis, artery treatment and in cosmetic fields. The HA with alkali metal ion, alkaline earth metal ion (for example, the magnesium ion), aluminum ion, ammonium ion, and salt form of the replacement of the ammonium ion can be the carrier for assisting drug absorption (referring to Belgium Patent 904,547). The silver salt is used as the mycocide and the gold salt is used for treating the rheumatoid arthritis among the heavy metal salt of the HA (referring to WO 87/05517).
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system. The related drugs are described as follows:
1. Steroids, specifically glucocorticoids, reduce inflammation or swelling by binding to glucocorticoid receptors. These drugs are often referred to as corticosteroids.
2. Non-steroidal anti-inflammatory drugs (NSAIDs) alleviate pain by counteracting the cyclooxygenase (COX) enzyme. On its own, COX enzyme synthesizes prostaglandins, creating inflammation. In whole, the NSAIDs prevent the prostaglandins from ever being synthesized, which reduces or eliminates the pain. Some common examples of NSAIDs are: aspirin, ibuprofen, and naproxen. The newer specific COX-inhibitors, although it is presumed, sharing a similar mode of action, are not classified together with the traditional NSAIDs.
3. ImSAIDs were discovered to have diverse biological properties, including anti-inflammatory properties. ImSAIDs work by altering the activation and migration of inflammatory cells, which are immune cells responsible for amplifying the inflammatory response (Bao F, John S M, Chen Y, Mathison R D, Weaver L C. The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. Neuroscience., 2006, 140(3):1011-22; Epub on 2006 Apr. 3). The ImSAIDs represent a new category of anti-inflammatory drugs and are unrelated to steroid hormones or non-steroidal anti-inflammatory drugs.
U.S. Pat. No. 6,159,955 discloses a method of treating aphthous ulcers comprising administration of an effective amount of a composition comprising a NSAID and a formulation of hyaluronic acid selected from hyaluronic acid, pharmaceutically acceptable salts thereof, fragments thereof and/or subunits thereof. However, it did not emphasize the less dose of the NSAID being used, whereas mesalamine does not belong to NSAID.
The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin, covered in epithelium, and involved in absorption (gastrointestinal tract) and secretion (gastrointestinal and respiratory tract). They line cavities that are exposed to the external environment and internal organs and contiguous with skin at several body areas: at the nostrils, the mouth, the lips, the eyelids, the ears, the genital area, and the anus. The sticky, thick fluid secreted by the mucous membranes and glands is termed mucus. The term mucous membrane refers to where they are found in the body and not every mucous membrane secretes mucus.
Conjunctivitis refers to inflammation of the conjunctiva (the outermost layer of the eye and the inner surface of the eyelids).
Otitis is a general term for inflammation or infection of the ear, in both humans and other animals.
Rhinitis is defined as inflammation of the nasal membranes and is characterized by a symptom complex that consists of any combination of the following: sneezing, nasal congestion, nasal itching, and rhinorrhea. The eyes, ears, sinuses, and throat can also be involved. US patent application 20050107330 disclosed a pharmaceutical composition for curative topical treatment of rhinitis comprising at least one acidic glycosaminoglycan. But this invention also contains at least one sympathomimetic suitable for topical application and having vasoconstrictor action or detumescent action on the mucous membrane or its physiologically acceptable salts or derivatives. It did not disclose the technical concept that less dose of drug can be used in need by combining with HA.
Oral mucosa is the mucous membrane epithelium of the mouth. An oral ulcer is an open sore inside the mouth, or rarely a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. Once formed, the ulcer may be maintained by inflammation and/or secondary infection.
Bronchitis is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from the trachea into the lungs. Bronchitis can be divided into two categories, acute and chronic, each of which has unique etiologies, pathologies, and therapies. US patent application 20030171332 discloses a method of treating respiratory conditions by a polysaccharide capable of binding CD44. However, only one single species of HA could be involved and the prior art did not disclose a combination of HA and a drug, not to mention merely a less dose of drug being used.
The mucosa is the innermost layer of the gastrointestinal wall that is surrounding the lumen, or open space within the tube. This layer comes in direct contact with food bolus, and is responsible for absorption, digestion, and secretion which are the important processes in digestion.
Generally known as peptic ulcer, and also known as PUD or peptic ulcer disease, peptic ulcer is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract that is usually acidic and thus causes extreme pain. Ulcers can also be caused or worsened by drugs such as aspirin, Plavix (clopidogrel), ibuprofen, and other NSAIDs (non-steroid anti-inflammatory drugs).
Mesalamine, also known as Mesalazine or 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat inflammation of the digestive tract ulcerative colitis and mild-to-moderate Crohn's disease. Mesalamine is a bowel-specific aminosalicylate drug that acts locally in the gut and has its predominant actions there, thereby having few systemic side effects. As a derivative of salicylic acid, mesalamine is also thought to be an antioxidant that traps free radicals, which are potentially damaging byproducts of metabolism. Mesalamine is considered the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalamine (Lippencott's Illustrated Reviews: Pharmacology, 4th Ed. Finkel, Cubeddu and Clark). Mesalamine is formulated for oral ingestion as tablets or granules, and for rectal administration as a rectal suppository, suspension or enemas. The regular therapeutically effective dose of three commercial drugs of mesalamine is introduced herein. Retention enema rectally for adult with ulcerative proctitis (active, chronic) and proctosigmoiditis (active ulcerative): 4 gm retention enema rectally QD at bedtime (retain for 8 hours) for 3 to 6 weeks (Colasa®). For the treatment of mildly to moderately active ulcerative colitis: The usual dosage in adults is two 400-mg tablets to be taken three times a day for a total daily dose of 2.4 grams for a duration of 6 weeks (Asacol®). The recommended dosage for the induction of remission and the symptomatic treatment of mildly to moderately active ulcerative colitis is 1 g (4 PENTASA 250 mg capsules or 2 PENTASA 500 mg capsules) 4 times a day for a total daily dosage of 4 g. Treatment duration in controlled trials was up to 8 weeks. (PENTASA®). In a preferred embodiment, the drug is a steroid, prednisolone. The initial dose of prednisone varies depending on the condition being treated and the age of the patient. The starting dose may be from 5 to 60 mg per day and often is adjusted based on the response of the condition being treated (Prednesol®). In a preferred embodiment, the drug is a NSAID, Naproxen. For Rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: 250-500 mg Naproxen is administered orally twice daily and may be increased to 1.5 g/day of naproxen base for limited time period. (Naprosyn®).
With regards to interaction between molecules, intermolecular forces are first categorized into hydrogen bond and non-covalent bond. Hydrogen bonds are essentially electrostatic in nature, although the energy of hydrogen bond can be decomposed into additional contributions from polarization, exchange repulsion, charge transfer, and mixing. A hydrogen bond is the attractive force between a hydrogen atom and an electronegative atom, such as nitrogen, oxygen, or fluorine. The hydrogen bond is often described as a strong electrostatic dipole-dipole interaction. The most common hydrogen bonds in biological systems involve oxygen and nitrogen atoms.
As another kind of interaction between molecules, the noncovalent bond is the dominant type of interaction between supermolecules in supermolecular chemistry. Noncovalent bonds are critical in maintaining the three-dimensional structure of large molecules and are involved in many biological processes in which large molecules bind specifically but transiently to one another. The forces consist of four types: (1) dipole-dipole forces, (2) ion-dipole forces, (3) dipole-induced dipole force or Debye forces, and (4) instantaneous dipole-induced dipole forces or London dispersion forces. Molecular interactions are fundamentally electrostatic in nature and can be described by Coulomb's Law. Coulomb's law correctly describes forces that bind (1) electrons to nuclei in atoms, (2) atoms to atoms in molecules, and (3) molecules to molecules in liquids and solids. The detailed descriptions of such forces are common scientific knowledge which are omitted herein.